SUMMARY/ABSTRACT Biomedical investigators are experiencing a limitation in their collective ability to translate the remarkable basic science discoveries of the current era into the clinical arena?a divide appropriately termed ?the valley of death.? In our first cycle of funding, we developed a novel training program in bench-to-bedside research methodology designed to train the next generation of clinical and basic researchers in translational approaches to pulmonary vascular biology and medicine. Our first eight trainees have had considerable success in publications, grant funding, and securing academic positions; two of the trainees were underrepresented minorities and six were women. In response to feedback from our current trainees and advisory boards, and in an effort to address the increasing pressure from the NIH, political leaders, and the public to translate basic discovery into therapeutic applications that positively change lives, we will extend the scope of our program in this second cycle of funding to incorporate entrepreneurial training, including: 1) development of a novel joint University of Pittsburgh (ranked #5 in NIH funding)-Carnegie Mellon University MBA Program (ranked #1 in part-time programs) in Entrepreneurship; 2) elective rotations focused on commercialization of biotechnology; and 3) an expanded faculty that includes translational scientist-entrepreneurs. We have created separate milestone-driven Translational Tracks and Entrepreneurial Tracks, but retaining the option for trainees to customize an Individual Development Plan to include components of either track. Trainees will be co-mentored by faculty with complementary research approaches to provide comprehensive training, and projects focused on patient-oriented bench-to-bedside (T1) research, with constant attention to trainee career development. Our faculty include translationally-focused pulmonologists, cardiologists, vascular surgeons, and PhDs spanning basic science to entrepreneurship, with a history of scientific productivity in pulmonary vascular biology, excellent funding support, successful mentoring, and expertise from drug discovery to commercialization of biotechnology. Substantial institutional support and resources are available through endowments to the VMI and a translational program project grant directed by Dr. Gladwin. The proposed training program, leadership, advisory boards, training faculty, and infrastructure at the University of Pittsburgh are strongly positioned to build on an already rich bench-to-bedside translational training program and create a generation of researchers committed to spanning the ?valley of death? between basic research discoveries, clinical application, and commercial viability in pulmonary vascular disease.